Heterocyclic compounds

ABSTRACT

The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.

FIELD OF THE INVENTION

The present invention relates to novel N-substituted azaheterocycliccarboxylic acids and esters thereof in which a substituted alkyl chainforms part of the N-substituent or salts thereof, to methods for theirpreparation, to compositions containing them, and to their use for theclinical treatment of painful, hyperalgesic and/or inflammatoryconditions in which C-fibers play a pathophysiological role by elicitingneurogenic pain or inflammation. The invention also relates to the useof the present compounds for the treatment of insulin resistance innon-insulin-dependent diabetes mellitus (NIDDM) or aging, the presentcompounds knowing to interfere with neuropeptide containing C-fibres andhence inhibit the secretion and circulation of insulin antagonizingpeptides like CGRP or amylin.

BACKGROUND OF THE INVENTION

The nervous system exerts a profound effect on the inflammatoryresponse. Antidromic stimulation of sensory nerves results in localizedvasodilation and increased vascular permeability (Janecso et al. Br. J.Pharmacol. 1967, 31, 138-151) and a similar response is observedfollowing injection of peptides known to be present in sensory nerves.From this and other data it is postulated that peptides released fromsensory nerve endings mediate many inflammatory responses in tissueslike skin, joint, urinary tract, eye, meninges, gastro-intestinal andrespiratory tracts. Hence inhibition of sensory nerve peptide releaseand/or activity, may be useful in treatment of, for example arthritis,dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis,glaucoma, gastro-intestinal diseases or migraine.

Further, the potent effects of CGRP on skeletal muscle glycogen synthaseactivity and muscle glucose metabolism, together with the notion thatthis peptide is released from the neuromuscular junction by nerveexcitation, suggest that CGRP may play a physiological role in skeletalmuscle glucose metabolism by directing the phosphorylated glucose awayfrom glycogen storage and into the glycolytic and oxidative pathways(Rossetti et al. Am. J. Physiol. 264, E1-E10, 1993). This peptide mayrepresent an important physiological modulator of intracellular glucosetrafficking in physiological conditions, such as exercise, and may alsocontribute to the decreased insulin action and skeletal muscle glycogensynthase in pathophysiological conditions like NIDDM or aging-associatedobesity (Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulatingplasma levels of CGRP are markedly increased. Hence inhibition ofrelease and/or activity of the neuropeptide CGRP may be useful in thetreatment of insulin resistance related to type 2 diabetes or aging.

In U.S. Pat. No. 4,383,999 and No. 4,514,414 and in EP 236342 as well asin EP 231996 some derivatives ofN-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids areclaimed as inhibitors of GABA uptake. In EP 342635 and EP 374801,N-substituted azaheterocyclic carboxylic acids in which an oxime ethergroup and vinyl ether group forms part of the N-substituent respectivelyare claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO9220656, N-substituted azacyclic carboxylic acids are claimed as GABAuptake inhibitors. EP 221572 claims that1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.

DESCRIPTION OF THE INVENTION

The present invention relates to novel N-substituted azaheterocycliccarboxylic ##STR1## wherein R¹ and R² independently are hydrogen,halogen, trifluoromethyl, hydroxy, C₁₋₆ -alkyl or C₁₋₆ -alkoxy; and

Y is --CH₂ --N--CH₂ --, --CH₂ --N--CH₂ --, --(C═O)--N--CH₂ --, --CH₂--N--(C═O)--, --CH₂ --C═CH--, --CH═C--CH₂ --, --CH₂ --CH--CH₂ --, --CH₂--CH--CH₂ --, --CH₂ --C═CH--, --CH═C--CH₂ --, --O--CH--CH₂ --, --CH₂--CH--O--, --S--CH--CH₂ -- or --CH₂ --CH--S-- wherein only theunderscored atoms participate in the ring system; and

X is --O--, --S--, --C(R⁶ R⁷)--,--CH₂ CH₂ --, --CH═CH--CH₂ --, --CH₂--CH═CH--, --CH₂ --(C═O)--, --(C═O)--CH₂ --, --CH₂ CH₂ CH2--, --CH═CH--,--N(R⁸)--(C═O)--, --(C═O)--N(R⁸)--, --O--CH₂ --, --CH₂ --O--, --S--CH₂--, --CH₂ --S--, --(C═O)--, --N(R⁹)--or --(S═O)--wherein R⁶, R⁷, R⁸ and

R⁹ independently are hydrogen or C₁₋₆ -alkyl; and

q is 0 or 1; and

p is 0 or 1; and

r is 1, 2 or 3; and

m is 1 or 2; and

n is 1 when m is 1 and n is 0 when m is 2; and

R³ and R⁴ each represents hydrogen or may--when m is 2--togetherrepresent

a bond; and

R⁵ is --OH or C₁₋₆ -alkoxy;

or a pharmaceutically acceptable salt thereof.

The compounds of formula I may exist as geometric and optical isomersand all isomers and mixtures thereof are included herein. Isomers may beseparated by means of standard methods such as chromatographictechniques or fractional crystallization of suitable salts.

Preferably, the compounds of formula I exist as the individual geometricor optical isomers.

The compounds according to the invention may optionally exist aspharmaceutically acceptable acid addition salts or--when the carboxylicacid group is not esterified--as pharmaceutically acceptable metal saltsor--optionally alkylated-ammonium salts.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartrate, oxalate or similarpharmaceutically acceptable inorganic or organic acid addition salts,and include the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) which are hereby incorporated byreference.

The term "C₁₋₆ -alkyl" as used herein, alone or in combination, refersto a straight or branched, saturated hydrocarbon chain having 1 to 6carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1,2-dimethylpropyl,2,2-dimethylpropyl and 1,2,2-trimethylpropyl.

The term "C₁₋₆ -alkoxy" as used herein, alone or in combination, refersto a straight or branched monovalent substituent comprising a C₁₋₆-alkyl group linked through an ether oxygen having its free valence bondfrom the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy,ethoxy, propoxy, isopropoxy, butoxy, pentoxy.

The term "halogen" means fluorine, chlorine, bromine or iodine.

Illustrative examples of compounds encompassed by the present inventioninclude:

(R)-1-(3-(6,11-Dioxo-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(5,11-Dihydro-10H-dibenzo b,e!1,4!diazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11H-Dibenz b,f!1,4!thiazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11H-Dibenz b,f!1,4!oxazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11H-Dibenzo b,f!1,4!oxathiepin-11-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11H-Dibenzo b,e!1,4!dithiepin-11-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11 H-Dibenz b,e!1,4!oxathiepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11,12-Dihydro-10H-dibenz b,g!1,5!oxazocin-11-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11,12-Dihydro-10H-dibenzo b,g!1,5!thiazocin-11-yl)-1-propyl)-3-piperidinecarboxylic acid;

1-(3-(11,12-Dihydro-6H-dibenzb,f!azocin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

1-(3-(11,12-Dihydro-5H-dibenzoa,e!cycloocten-5-ylidene)-1-propyl)-3-piperidine-carboxylic acid;

1-(3-(6-Oxo-11,12-dihydro-5H-dibenzb,f!azocin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

1-(3-(7,12-Dihydro-6H-dibenzoa,d!cycloocten-6-ylidene)-1-propyl)-3-piperidinecarboxylic acid;

1-(3-(5-Methyl-5,11-dihydro-dibenzb,f!azepin-10-ylidene)-1-propyl)-3-piperidinecarboxylic acid;

1-(3-(6-Oxo-5,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11-Oxo-10,11-dihydro-5H-dibenzo b,e!1,4!diazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(6-Oxo-11,12-dihydro-5H-dibenzb,f!azocin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(10,11-Dihydro-dibenz b,f!1,4!oxazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(5,6,11,12-Tetrahydro-dibenzb,f!azocin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11-Oxo-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidine-carboxylic acid;

(R)-1-(3-(5-Methyl-dibenzb,f!azepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(6,7-Dihydro-5H-dibenz b,g!1,5!oxazocin-6-yl)-1-propyl)-3-piperidine-carboxylic acid;

(R)-1-(3-(11,12-Dihydro-dibenza,e!cycloocten-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

As used herein, the term "patient" includes any mammal which couldbenefit from treatment of neurogenic pain or inflammation or insulinresistance in NIDDM. The term particularly refers to a human patient,but is not intended to be so limited.

It has been demonstrated that the novel compounds of formula I inhibitneurogenic inflammation which involves the release of neuropeptides fromperipheral and central endings of sensory C-fibres. Experimentally thiscan be demonstrated in animal models of formalin induced pain or pawoedema (Wheeler and Cowan, Agents Actions 1991, 34, 264-269) in whichthe novel compounds of formula I exhibit a potent inhibitory effect.Compounds of formula I may be used to treat all painful, hyperalgesicand/or inflammatory conditions in which C-fibers play apathophysiological role by eliciting neurogenic pain or inflammation,i.e.:

Acutely painful conditions exemplified by migraine, postoperative pain,burns, bruises, post-herpetic pain (Zoster) and pain as it is generallyassociated with acute inflammation; chronic, painful and/or inflammatoryconditions exemplified by various types of neuropathy (diabetic,post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis,gout, inflammatory bowel disease, prostatitis, cancer pain, chronicheadache, coughing, asthma, chronic pancreatitis, inflammatory skindisease including psoriasis and autoimmune dermatoses, osteoporoticpain.

Further, it has been demonstrated that the compounds of general formulaI improves the glucose tolerance in diabetic ob/ob mice and that thismay result from the reduced release of CGRP from peripheral nervousendings. Hence the compounds of general formula I may be used in thetreatment of NIDDM as well as aging-associated obesity. Experimentallythis has been demonstrated by the subcutaneous administration of glucoseinto ob/ob mice with or without previous oral treatment with a compoundof general formula I.

The compounds of formula I may be prepared by the following method:##STR2##

A compound of formula II wherein R¹, R², X, Y, p, q and r are as definedabove and W is a suitable leaving group such as halogen, p-toluenesulphonate or mesylate may be reacted with an azaheterocyclic compoundof formula III wherein R³, R⁴, R⁵, m and n are as defined above. Thisalkylation reaction may be carried out in a solvent such as acetone,dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate,tetrahydrofuran (THF) or toluene in the presence of a base e.g.potassium carbonate and a catalyst, e.g. an alkali metal iodide at atemperature up to reflux temperature for the solvent used for e.g. 1 to120 h. If esters have been prepared in which R⁵ is alkoxy, compounds offormula I wherein R⁵ is OH may be prepared by hydrolysis of the estergroup, preferably at room temperature in a mixture of an aqueous alkalimetal hydroxide solution and an alcohol such as methanol or ethanol, forexample, for about 0.5 to 6 h.

Compounds of formula II and III may readily be prepared by methodsfamiliar to those skilled in the art.

Under certain circumstances it may be necessary to protect theintermediates used in the above methods e.g. a compound of formula IIIwith suitable protecting groups. The carboxylic acid group can, forexample, be esterified. Introduction and removal of such groups isdescribed in "Protective Groups in Organic Chemistry" J. F. W. McOrnieed. (New York, 1973).

PHARMACOLOGICAL METHODS

Formalin induced pain or paw oedema

Values for in vivo inhibition of formalin induced pain or oedema for thecompounds of the present invention were assessed in mice essentially bythe method of Wheeler-Aceto and Cowan (Agents Action 1991, 34, 265-269).

About 20 g NMRI female mice were injected 20 ml 1% formalin into theleft hind paw. The animals were then placed on a heated (31° C.) table,and the pain response was scored. After 1 h they were killed and bled.Left and right hind paws were removed and the weight difference betweenthe paws was used as indication of the oedema response of the formalininjected paw.

Reduced release of CGRP

ob/ob female mice, 16 weeks of age, where injected glucose (2g/kg)subcutaneously. At times hereafter blood glucose was determined in tailvenous blood by the glucose oxidase method. At the end of the study theanimals were decapitated and trunck blood collected. Immunoreactive CGRPwas determined in plasma by radio-immuno-assay. Two groups of animalswere used. The one group was vehicle treated, whereas the other groupreceived a compound of formula I via drinking water (100 mg/I) for fivedays before the test.

Values for inhibition of formalin induced pain response for somerepresentative compounds are recorded in table 1.

                  TABLE 1                                                         ______________________________________                                        Inhibition of formalin induced pain response at 0.1 mg/kg                     Example no.   % Pain inhibition                                               ______________________________________                                        1             13                                                              2             34                                                              3             36                                                              4             28                                                              6             22                                                              ______________________________________                                    

For the above indications the dosage will vary depending on the compoundof formula I employed, on the mode of administration and on the therapydesired. However, in general, satisfactory results are obtained with adosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mgto about 500 mg of compounds of formula I, conveniently given from 1 to5 times daily, optionally in sustained release form. Usually, dosageforms suitable for oral administration comprise from about 0.5 mg toabout 1000 mg, preferably from about 1 mg to about 500 mg of thecompounds of formula I admixed with a pharmaceutical carrier or diluent.

The compounds of formula I may be administered in a pharmaceuticallyacceptable acid addition salt form or where possible as a metal or alower alkylammonium salt. Such salt forms exhibit approximately the sameorder of activity as the free base forms.

This invention also relates to pharmaceutical compositions comprising acompound of formula I or a pharmaceutically acceptable salt thereof and,usually, such compositions also contain a pharmaceutical carrier ordiluent. The compositions containing the compounds of this invention maybe prepared by conventional techniques and appear in conventional forms,for example capsules, tablets, solutions or suspensions.

The pharmaceutical carrier employed may be a conventional solid orliquid carrier. Examples of solid carriers are lactose, terra alba,sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate andstearic acid. Examples of liquid carriers are syrup, peanut oil, oliveoil and water.

Similarly, the carrier or diluent may include any time delay materialknown to the art, such as glyceryl monostearate or glyceryl distearate,alone or mixed with a wax.

If a solid carrier for oral administration is used, the preparation canbe tabletted, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

Generally, the compounds of this invention are dispensed in unit dosageform comprising 50-200 mg of active ingredient in or together with apharmaceutically acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 1-500 mg/day,e.g. about 100 mg per dose, when administered to patients, e.g. humans,as a drug.

A typical tablet which may be prepared by conventional tablettingtechniques contains

    ______________________________________                                        Core:                                                                         Active compound (as free compound                                                                     100 mg                                                or salt thereof)                                                              Colloidal silicon dioxide (Areosil ®)                                                             1.5 mg                                                Cellulose, microcryst. (Avicel ®)                                                                 70 mg                                                 Modified cellulose gum (Ac-Di-Sol ®)                                                              7.5 mg                                                Magnesium stearate                                                            Coating:                                                                      HPMC                    approx. 9 mg                                          *Mywacett ® 9-40 T  approx. 0.9 mg                                        ______________________________________                                         *Acylated monoglyceride used as plasticizer for film coating.            

The route of administration may be any route which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral e.g. rectal, transdermal,subcutaneous, intranasal, intramuscular, topical, intravenous,intraurethral, ophthalmic solution or an ointment, the oral route beingpreferred.

EXAMPLES

The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, which,however, are not to be construed as limiting.

Hereinafter, TLC is thin layer chromatography, CDCl₃ is deuteriochloroform and DMSO-d₆ is hexadeuterio dimethylsulfoxide. The structuresof the compounds are confirmed by either elemental analysis or NMR,where peaks assigned to characteristic protons in the title compoundsare presented where appropriate. ¹ H NMR shifts (⁶⁷ H) are given inparts per million (ppm). M.p. is melting point and is given in ° C. andis not corrected. Column chromatography was carried out using thetechnique described by W. C. Still et al, J. Org. Chem. (1978), 43,2923-2925 on Merck silica gel 60 (Art. 9385). Compounds used as startingmaterials are either known compounds or compounds which can readily beprepared by methods known per se.

Example 1 (R)-1-(3-(11-Oxo-10,11-dihydro-5H-dibenzo b,e!1,4!diazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride##STR3##

To a solution of 11-oxo-10,11-dihydro-5H-dibenzo b,e! 1,4!diazepine(12.1 g, 0.058 mol, prepared as described in Synthesis, 1985, 550) indry N,N-dimethylformamide (150 ml) kept under an atmosphere of nitrogen,sodium hydride (2.8 g, 0.069 mol, 60% dispersion in oil) was added andthe reaction mixture was stirred for 1 hour. 1-Bromo-3-chloropropane(10.9 g, 0.069 mol) was slowly added and the mixture was stirredovernight. The reaction mixture was quenched with water (200 ml) andextracted with diethyl ether (2×250 ml). The combined organic extractswere washed with water (3×300 ml), dried (MgSO₄) and the solvent wasevaporated in vacuo. The solid was washed with heptane (100 ml),filtered off and dried, affording 11.1 g (67%) of10-(3-chloro-propyl)-5,10-dihydro-dibenzo b,e! 1,4!diazepin-11-one.

M.p. 127°-131° C.

¹ H NMR (200 MHz, CDCl₃)δ_(H) 2.15 (m, 2H), 3.61 (t, 2H), 4.25 (t, 2H),5.50 (bs, 1H, NH), 6.81 (d, 1H), 6.91-7.13 (m, 4H), 7.20-7.26 (m, 2H),7.82 (dd, 1H).

A mixture of the above chloride (4.0 g, 0.014 mol),(R)-3-piperidinecarboxylic acid ethyl ester tartrate (8.6 g, 0.028 mol),potassium carbonate (11,7 g, 0.084 mol), potassium iodide (4.6 g, 0.028mol) and methyl ethyl ketone (100 ml) was heated at reflux temperaturefor 18 hours under an atmosphere of nitrogen. The cooled reactionmixture was quenched with water (100 ml) and extracted with diethylether (100 ml). The organic extract was washed with water (2×80 ml),saturated ammonium chloride (80 ml), dried (MgSO₄), filtered and thesolvent was evaporated in vacuo. The crude product (7 g) was purified bycolumn chromatography on silica gel (600 ml) using ethyl acetate aseluent. This afforded 3.1 g (55%) of(R)-1-(3-(11-oxo-10,11-dihydro-5H-dibenzo b,e!-1,4!diazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester asan oil.

TLC: R_(f) =0.24 (SiO₂ ; ethyl acetate).

¹ H NMR (200 MHz, CDCl₃)δ_(H) 1.24 (t, 3H), 1.40 (m, 2H), 1.61 (m, 2H),1.85 (m, 4H), 2.17 (d, 1H), 2.39 (m, 4H), 2.62 (bd, 1H), 2.82 (bd, 1H),4.10 (q, 2H), 5.59 (bs, 1H, NH), 6.81 (d, 1H), 6.91-7.10 (m, 4H),7.19-7.30 (m, 2H), 7.81 (dd, 1H).

The above ethyl ester (2.9 g, 7 mmol) was dissolved in a mixture ofethanol (50 ml) and water (30 ml). Sodium hydroxide (0.34 g, 9 mmol) wasadded and the reaction mixture was stirred for 40 hours at roomtemperature. The solvent was evaporated in vacuo, and water (150 ml) wasadded. The aqueous mixture was washed with diethyl ether (2×100 ml),acidified with concentrated hydrochloric acid and washed withdichloromethane (3×100 ml). The aqueous phase was evaporated in vacuo.The residue was suspended in a mixture of 2-propanol (10 ml) and diethylether (50 ml) and stirred for 60 hours at room temperature. Theprecipitate was filtered off, washed with diethyl ether and dried invacuo. Yield 1.57 g (53%) of the title compound as an amorphous powder.

HPLC retention time=5.65 min. (5 μm C18 4×250 mm column, eluting with amixture of water and acetonitril (7:3) containing phosphoric acid andbuffered to pH=3 with triethylamine over 20 minutes at 35° C.). ¹ H NMR(400 MHz, DMSO-d₆) δ_(H) 1.27 (m, 1H), 1.50 (d, 1H), 1.59-1.78 (m, 5H),1.91 (m, 1H), 2.22 (t, 2H), 2.57 (d, 1H), 2.85 (d, 1H), 3.38 (m, 1H),400 (t, 2H), 6.94 (t, 1H), 7.10 (m, 3H), 7.20 (m, 1H), 7.32 (m, 2H),7.59 (d, 1H), 8.02 (s, 1H, NH).

By a similar procedure as described in Example 1 the following compoundhas been prepared:

Example 2 (R)-1-(3-(6-Oxo-11,12-dihydro-5H-dibenzb,f!azocin-5-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride##STR4##

The title compound was prepared by a similar procedure as described inExample 1.

HPLC retention time=7.84 min (5 μm C18 4×250 mm column, eluting for 20minutes at 30° C. with a mixture of water and acetonitril (7:3)containing phosphoric acid and buffered to pH=3 with triethylamine).

M.p. 223°-225° C.

MS(El) 392.2 (M⁺ --HCl, 10%)

Example 3 (R)-1-(3-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidine-carboxylic acid hydrochloride##STR5##

In a 100 ml round bottom flask equipped with magnetically stirring,thermometer, reflux condenser and addition funnel,6,11-dihydro-5H-dibenz b,e!azepine (1.0 g, 5,1 mmol, prepared in asimilar way as described in Coll. Czech. Chem. Commun., 23, 1958, 1330)was dissolved in dry toluene (25 ml). 3-Chloropropionyl chloride (0.78g, 6,1 mmol) was added slowly. When addition was complete, the reactionmixture was heated at 95° C. for 30 minutes and then allowed to cool toroom temperature. With stirring, 0.2N sodium hydroxide (2.5 ml) wasadded. More toluene (50 ml) was added and the phases were separated. Theorganic phase was washed with 0.2N sodium hydroxide (10 ml) until pH>10,and then with water (3×10 ml) and brine (10 ml). After drying (MgSO₄),the solvent was evaporated in vacuo affording3-chloro-1-(6,11-dihydro-5H-dibenz b,e!azepin-5-yl)-1-propanone as anoil which was obtained in quantitative yield and used for furtherreactions without purification.

A 1.0M tetrahydrofuran solution of lithium aluminum hydride (9.8 ml) wasintroduced under a nitrogen atmosphere to a dry 100 ml three-neckedroundbottom flask using a syringe. Concentrated sulphuric acid (0.264ml) was cautiously added under cooling on an ice bath, and the resultingsolution was stirred at room temperature for 1.5 hour. The above amidewas dissolved in dry tetrahydrofuran (9.8 ml) and slowly added. Thereaction mixture was stirred overnight. The reaction was quenched byaddition of water (0.4 ml), 4N sodium hydroxide (0.4 ml) and water (1.2ml), successively. The resulting mixture was filtered (hyflo) and thefiltercake was washed with diethyl ether and ethyl acetate. The solventwas evaporated affording 5-(3-chloropropyl)-6,11-dihydro-5H-dibenzob,e!azepine, which was used for further reaction without purification.

A solution of potassium iodide (4.5 g, 0.027 mol) in methyl ethyl ketone(75 ml) was heated at reflux temperature for 1 hour. A solution of theabove chloride (1.2 g, 4.2 mmol) in methyl ethyl ketone (25 ml) wasadded and the reaction mixture was heated at reflux temperature for 2.75hours. (R)-3-Piperidinecarboxylic acid ethyl ester tartrate (1.87 g, 6.2mmol) and potassium carbonate (1.44 g, 0.01 mol) were added and themixture was heated at reflux temperature for 24 hours, and left stirringat room temperature for 48 hours. After filtration on filter aid(celite), the solvent was removed by evaporation. The residue waspurified by column chromatography on silica gel (125 g) using a mixtureof heptane and ethyl acetate (1:1) as eluent. This afforded 0.7 g (42%)of (R)-1-(3-(6,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as anoil.

TLC: R_(f) =0.19 (SiO₂ : heptane/ethyl acetate=1:1).

The above ester (0.66 g, 1.7 mmol) was dissolved in ethanol (10 ml) anda solution of sodium hydroxide (0.25 g) in water (2 ml) was added. Themixture was stirred at room temperature for 2 hours and concentratedhydrochloric acid (0.8 ml) was added. Dichloromethane (100 ml) wasadded, followed by water (50 ml) and the phases were separated. Theorganic phase was dried (MgSO₄) and the solvent evaporated in vacuo. Theresidue was stripped with acetone, suspended in isopropyl acetate andfiltered off. This afforded after drying, 0.5 g (74%) of the titlecompound as an amorphous solid.

HPLC retention time=20.41 minutes (5 μm C18 4×250 mm column, elutingwith a 20-80% gradient of 0.1% trifluoroacetic acid/acetonitrile and0.1% trifluoroacetic acid/water over 30 minutes at 35° C.).

Calculated for C₂₃ H₂₈ N₂ O₂, HCl, 0.25 H₂ O: C, 68.14%; H, 7.28%; N,6.91%; Found: C, 68.08%; H, 7.44%; N, 6.61%.

Example 4 (R)-1-(3-(6,11-Dioxo-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidine-carboxylic acid hydrochloride##STR6##

To a solution of 5H-dibenz b,e!azepine-6,11-dione (3.0 g, 0.013 mol) indry N,N-dimethylformamide (25 ml) kept under an atmosphere of nitrogen,sodium hydride (0.7 g, 0.027 mol, 60% dispersion in mineral oil) wasadded in portions and the reaction mixture was stirred for 1.5 hour.1-Bromo-3-chloropropane (5.0 g, 0.031 mol) dissolved inN,N-dimethylformamide was slowly added and the mixture was stirredovernight. Ammonium chloride (2.0 g, 0.04 mol) was added and stirringwas continued for 30 minutes. The solution was poured onto water (300ml) and the mixture was extracted with dichloromethane (2×200 ml). Thecombined organic extracts were dried (MgSO₄), filtered and the solventwas evaporated in vacuo. The residue was purified by columnchromatography on silica gel (150 g) using a mixture of heptane andethyl acetate (4:1) as eluent to give 3.1 g (79%) of5-(3-chloropropyl)-5H-dibenz b,e!azepine-6,11-dione as an oil.

TLC: R_(f) =0.48 (SiO₁ : heptane/ethyl acetate=1:1).

A solution of potassium iodide (10.0 g, 0.06 mol) in methyl ethyl ketone(180 ml) was heated at reflux temperature for 1 hour. A solution of theabove chloride (3.09 g, 0.01 mol) in methyl ethyl ketone (20 ml) wasadded and the reaction mixture was heated at reflux temperature for 2hours. After cooling to about 60° C., (R)-3-piperidinecarboxylic acidethyl ester tartrate (4.50 g, 0.015 mol) and potassium carbonate (3.46g, 0.025 mol) were added and the mixture was heated at refluxtemperature for 48 hours. After cooling and filtration on filter aid(hyflo) the solvent was removed by evaporation. The residue was purifiedby column chromatography on silica gel (125 g) using first a mixture ofheptane and ethyl acetate (1:1) to eluate the front running fractionsand then with a mixture of heptane and ethyl acetate (2:3) as eluent.This afforded 1.21 g (29%) of(R)-1-(3-(6,11-dioxo-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as anoil.

TLC: R_(f) =0.05 (SiO₂ : heptane/ethyl acetate=2:3).

To the above ester (0.60 g, 1.4 mmol) in ethanol (10 ml), a solution ofsodium hydroxide (0.35 g) in water (2 ml) was added. The mixture wasstirred at room temperature for 2 hours and then concentratedhydrochloric acid (1 ml) was added. Dichloromethane (100 ml) was added,followed by water (50 ml) and the phases were separated. The organicphase was dried (MgSO₄) and the solvent was evaporated in vacuo.Subsequent re-evaporation with acetone and addition of isopropyl acetateafforded, after filtration and drying 0.2 g (23%) of the title compoundas a solid.

HPLC retention time=16.76 minutes (5 μm C18 4×250 mm column, elutingwith a 20-80% gradient of 0.1% trifluoroacetic acid/acetonitrile and0.1% trifluoroacetic acid/water over 30 minutes at 35° C.).

¹ H NMR (400 MHz, DMSO-d₆) δ_(H) 1.35 (m, 1H), 1.50 (m, 1H), 1.61 (m,1H), 1.80 (m, 3H), 2.19 (m, 1H), 2.33 (m, 1H), 2.54 (m, 3H), 2.78 (d,1H), 2.93 (d, 1H), 3.39 (m, 2H), 4.50 (bs, 1H), 6.40 (t, 1H), 6.81 (d,1H), 6.93 (d, 1H), 7.27 -7.34 (m, 2H), 7.53 (t, 1H), 7.60 (t, 1H), 7.94(d, 1H), 8.70 (bs, 1H).

Example 5 (R)-1-(3-(10,11-Dihydro-dibenz b,f!1,4!oxazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride##STR7##

In a dry 250 ml three-necked flask equipped with reflux condenser andthermometer, lithium aluminum hydride (1.8 g, 0.047 mol) was suspendedin dry diethyl ether (75 ml) under a nitrogen atmosphere. Cautiously,10,11-dihydrodibenz b,f! 1,4!oxazepin-11-one (5.0 g, 0.024 mol) wasadded in portions. The mixture was heated at reflux temperature for 5hours, cooled to room temperature and left stirring overnight. Thereaction mixture was quenched by cautious addition of water (1.8 ml), 4Nsodium hydroxide (1.8 ml) and finally water (5.4 ml). Diethyl ether andtoluene were added and the mixture was filtered. The filtercake waswashed with diethyl ether, toluene and ethyl acetate, successively. Thefiltrate was evaporated until dryness, affording 4.55 g (96%) of10,11-dihydrodibenz b,f! 1,4!oxazepine.

The above tricycle (4.0 g, 0.02 mol) was dissolved in toluene (100 ml)and 3-chloropropionyl chloride (3.12 g, 0.025 mol) was added. Thereaction mixture was heated at 95° C. for 30 minutes and left stirringfor 1 hour. 0.2N Sodium hydroxide (10 ml) was added and the phases wereseparated. Toluene (200 ml) was added and the organic phase was washedwith 0.2N sodium hydroxide (50 ml), water (3×50 ml) and brine (50 ml).The organic phase was dried (MgSO₄), filtered and the solventevaporated. This afforded 3-chloro-1-(10, 11 -dihydro-dibenz b,f!1,4!oxazepin-10-yl)-1-propanone in quantitative yield.

A 1.0M tetrahydrofuran solution of lithium aluminium hydride (38.4 ml,0.0384 mol) was introduced into a dry 500 ml three-necked flask.Cautiously, concentrated sulphuric acid (1.84 ml, 0.019 tool) was addeddropwise upon cooling on an icebath and then the mixture was stirred for1.5 hour at room temperature. A solution of the above chloride in drytetrahydrofuran (38.4 ml) was added dropwise and the reaction mixturewas stirred for 1.5 hour. The reaction mixture was subsequently quenchedby cautious addition of water (1.5 ml), 4N sodium hydroxide (1.5 ml) andfinally water (4.5 ml), and the resulting suspension was left stirringovernight. The precipitated salt was filtered off and washed withdiethyl ether, toluene and ethyl acetate. The filtrate was evaporateduntil dryness to give 4.8 g of crude10-(3-chloropropyl)-10,11-dihydro-dibenz b,f! 1,4!oxazepine.

A solution of potassium iodide (16.0 g, 0.1 mol) in methyl ethyl ketone(180 ml) was heated at reflux temperature for 1 hour. A solution of theabove chloride (3.14 g, 0.012 mol) in methyl ethyl ketone (20 ml) wasadded and the reaction mixture was heated at reflux temperature for 2.5hours. (R)-3-Piperidinecarboxylic acid ethyl ester tartrate (7.2 g,0.024 mol) and potassium carbonate. (5.53 g, 0.04 mol) were added andthe mixture was heated at reflux temperature for 72 hours. After coolingand filtration on filter aid (celite) the solvent was removed byevaporation. The residue was purified by column chromatography on silicagel (200 g) using a mixture of heptane and ethyl -acetate (1:1) aseluent. This afforded 4.5 g (99%) of (R)-1-(3-(10,11-dihydro-dibenz b,f!1,4!oxazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester asan oil.

TLC: R_(f) =0.18 (SiO₂ : heptane/ethyl acetate=1:1).

The above ester (1.0 g, 0.0025 mol) was dissolved in ethanol (15 ml) anda solution of sodium hydroxide (0.38 g) in water (3 ml) was added. Themixture was stirred at room temperature for 2 hours and concentratedhydrochloric acid (1.2 ml) was added. Dichloromethane (150 ml) wasadded, followed by water (50 ml) and the phases were separated. Theorganic phase was dried (MgSO₄) and the solvent evaporated in vacuo.Subsequent reevaporation with acetone and addition of a small amount ofacetone followed by isopropyl acetate afforded, after filtration anddrying 0.2 g (21%) of the title compound as a solid.

M.p. 185°-188° C.

Calculated for C₂₂ H₂₆ N₂ O₃, HCl, 0.75 H₂ O: C, 63.46%; H, 6.85%; N,6.73%; Found: C, 63.06%; H, 6.74%; N, 6.47%.

Example 6 (R)-1-(3-(5,6,11,12-Tetrahydro-dibenzb,f!azocin-5-yl)-1-propyl)-3-piperidinecarboxylic acid dihydrochloride##STR8##

To a solution of 5,6,11,12-tetrahydro-dibenz b,f!azocine hydrochloride(7.0 g, 0.029 mol) in dry tetrahydrofuran (100 ml) kept under anatmosphere of nitrogen, n-butyl lithium (22.2 ml, 0.06 mol, 2.7M inn-hexane) was added dropwise at 0° C. The reaction mixture was stirredat room temperature for 0.75 hour. A solution of 1-bromo-3-chloropropane(5.4 g, 0.034 mol) in dry tetrahydrofuran (100 ml) was added dropwise at0° C. and the reaction mixture was stirred at room temperature for 4hours. The reaction mixture was quenched with water (100 ml) andextracted with diethyl ether (100 ml). The organic extract was washedwith brine (80 ml), dried (MgSO₄), filtered, and the solvent wasevaporated in vacuo. Yield 7.7 g of crude5-(3-chloropropyl)-5,6,11,12-tetrahydro-dibenz b,f!azocine.

A mixture of the above chloride (4.7 g, 0.027 mol),(R)-3-piperidinecarboxylic acid ethyl ester tartrate (16.6 g, 0.054tool), dry potassium carbonate (22,3 g, 0.162 tool), potassium iodide(8.9 g, 0.054 mmol) and methyl ethyl ketone.(250 ml) was heated atreflux temperature for 66 hours under an atmosphere of nitrogen. Thecooled reaction mixture was quenched with water (250 ml) and extractedwith diethyl ether (250 ml). The organic extract was washed with water(2×80 ml), brine (80 ml), dried (MgSO₄), filtered and the solvent wasevaporated in vacuo. The crude product (12.4 g) was purified by columnchromatography on silica gel (800 ml) using a mixture of ethyl acetateand heptane (1:2) as eluent. This afforded 3.3 g (30%) of(R)-1-(3-(5,6,11,12-tetrahydro-dibenzb,f!azocin-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as anoil.

TLC: R_(f) =0.35 (SiO₂ : ethyl acetate/heptane=1:1).

The above ethyl ester (3.0 g, 7.38 mmol) was dissolved in a mixture ofethanol (30 ml) and water (30 ml). Sodium hydroxide (0.35 g, 8.85 mmol)was added and the reaction mixture was stirred for 18 hours at roomtemperature. The solvent was evaporated in vacuo and water (100 ml) wasadded. The aqueous mixture was washed with diethyl ether (2×100 ml) andacidified with concentrated hydrochloric acid. The aqueous phase wasevaporated in vacuo and the residue was suspended in 2-propanol (25 ml)and filtered. The filtrate was evaporated in vacuo and the residue wasdissolved in acetone (20 ml) and evaporated in vacuo. The residue wasdissolved in dichloromethane (100 ml) and filtered. The filtrate wasevaporated in vacuo and the residue was suspended in a mixture ofacetone (10 ml) and diethyl ether (5 ml) and stirred for 18 hours atroom temperature. The precipitate was filtered off, washed with diethylether and dried to afford 1.1 g (36%) of the title compound as a solid.

M.p. 200°-203° C.

Calculated for C₂₄ H₃₀ N₂ O₂, 2HCl, H₂ O: C, 61.40%; H, 7.30%; N, 5.97%;Found: C, 61.26%; H, 7.60%; N, 5.85%.

Example 7 (R)-1-(3-(11-Oxo-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidine-carboxylic acid hydrochloride##STR9##

To a mixture of 5H-dibenz b,e!azepine-6,11-dione (5.0 g, 22.4 mmol),ethylene glycol (12.5 ml, 0.224 mol) and nitromethane (60 ml) in drytoluene (100 ml) kept under an atmosphere of nitrogen, triflic acid (0.4ml, 4.5 mmol) was added dropwise. The reaction mixture was heated atreflux temperature for 3 days with a water separator. The cooledreaction mixture was quenched with water (100 ml) and extracted withethyl acetate (80 ml). The organic extract was washed with water (3×80ml), dried (MgSO₄), filtered and the solvent was evaporated in vacuo.This afforded 5.16 g (86%) of 5H-dibenz b,e!azepin-6,11-dione11-ethylene ketal as a solid.

TLC: R_(f) =0.32 (SiO₂ ; heptane/ethyl acetate=1:1).

¹ H NMR (200 MHz, DMSO-d₆)δ_(H) 3.75 (m, 2H), 4.17 (t, 2H), 7.06-7.80(m, 8H), 10.58 (s, 1H).

To a solution of the above ketal (4.5 g, 0.0168 tool) in dryN,N-dimethyl-formamide (75 ml) kept under an atmosphere of nitrogen,sodium hydride (0.8 g, 0.02 tool, 60 % dispersion in mineral oil) wasadded in portions and the reaction mixture was stirred for 0.5 hour. Asolution of 2-(3-bromo-1-propyloxy)tetrahydro-2H-pyran (4.5 g, 0.02 mol)in N,N-dimethylformamide was added slowly and the reaction mixture wasstirred for 6 days. The reaction mixture was poured into water (100 ml)and the mixture was extracted with diethyl ether (2×100 ml). Thecombined organic extracts were washed with saturated ammonium chloride(3×100 ml), dried (MgSO₄), filtered and the solvent was evaporated invacuo. This afforded a residue (6.7 g) which was purified by columnchromatography on silica gel (800 ml) using a mixture of heptane andethyl acetate (2:1) as eluent. This afforded 4.4 g (64%) of5-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propyl)-5H-dibenzb,e!azepin-6,11-dione 11-ethylene ketal as an oil.

TLC: R_(f) =0.39 (SiO₂ : heptane/ethyl acetate=1:1).

In a dry 100 ml three-necked flask equipped with reflux condenser andthermometer, lithium aluminum hydride (0.4 g; 10.5 mmol) was suspendedin dry diethyl ether (50 ml) under a nitrogen atmosphere. Cautiously, asolution of 5-(3-tetrahydro-2H-pyran-2-yloxy)-1 -propyl)-5H-dibenzb,e!azepin-6,11-dione 11-ethylene ketal (3.9 g) in diethyl ether (30 ml)and tetrahydrofuran (20 ml) was added dropwise. The mixture was heatedat reflux temperature for 3 hours, cooled to room temperature andquenched by cautious addition of water (0.5 ml) and 50% sodium hydroxide(0.5 ml), and filtered. The filtrate was evaporated until drynessaffording 3.9 g of an oil which was purified by column chromatography onsilica gel (600 ml) using a mixture of heptane and ethyl acetate (4:1)as eluent. This afforded 1.9 g (50%) of 5-(3-tetrahydro-2H-pyran-2-yloxy)-1-propyl)-5,6-dihydro-dibenz b,e!azepin-11-one ethylene ketalas an oil.

TLC: R_(f) =0.43 (SiO₂ : heptane/ethyl acetate=2:1).

The above ketal (1.8 g, 4.55 mmol) was dissolved in 85% ethanol (20 ml)and concentrated hydrochloric acid (1 ml) was added. The reactionmixture was heated at reflux temperature for 3.5 hours. Water (100 ml)was added and the mixture was extracted with diethyl ether (2×100 ml).The combined organic extracts were washed with water (100 ml) and brine(100 ml), dried (MgSO₄) and filtered. The solvent was evaporated invacuo to give 5-(3-hydroxy-1-propyl)-5,6-dihydro-5H-dibenzb,e!azepin-11-one in quantitative yield.

M.p. 113°-115° C.

To a mixture of the above alcohol (1.0 g, 3.7 mmol) and triethylamine (1ml) in dichloromethane (30 ml), methanesulfonyl chloride (0.64 g, 5.61mmol) dissolved in dichloromethane (10 ml) was added dropwise at 15° C.The reaction mixture was stirred at room temperature for 2 hours andquenched with water. The organic phase was separated, dried (MgSO₄),filtered and evaporated in vacuo. This afforded methanesulfonic acid3-(11-oxo-5,6-dihydro-dibenz b,e!azepin-5-yl)-l-propyl ester as an oil.

TLC: R_(f) =0.22 (SiO₂ : heptane/ethyl acetate=1:1).

A mixture of the above methanesulfonate (1.3 g, 3.8 mmol),(R)-3-piperidinecarboxylic acid ethyl ester tartrate (2.3 g, 7.5 mmol),dry potassium carbonate (3,1 g, 23 mmol), and methyl ethyl ketone (50ml) was heated at reflux temperature for 18 hours under an atmosphere ofnitrogen. Potassium iodide (0.2 g, 1.2 mmol) was added and the mixturewas heated at reflux temperature for 7 hours. After cooling, thereaction mixture was quenched with water (50 ml) and extracted withethyl acetate (50 ml). The organic extract was washed with water (2×80ml), brine (80 ml), dried (MgSO₄), filtered and the solvent wasevaporated in vacuo. The crude product (1.4 g) was purified by columnchromatography on silica gel (400 ml) using first a mixture of ethylacetate and heptane (1:3) and then a mixture of ethyl acetate andtriethylamine (96:4) as eluents. This afforded 0.9 g (59%) of(R)-1-(3-(11-oxo-5,6-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as anoil.

TLC: R_(f) =0.12 (SiO₂ : ethyl acetate/heptane=2:1).

To the above ester (0.8 g, 2.0 mmol) dissolved in ethanol (25 ml) asolution of sodium hydroxide (94 mg, 2.4 mmol) in water (15 ml) wasadded and the mixture was stirred at room temperature for 18 hours. Thesolvent was evaporated and water (75 ml) was added to the residue. Theaqueous phase was washed with diethyl ether (2×75 ml), acidified to pH 1with concentrated hydrochloric acid and washed with dichloromethane(3×100 ml). The aqueous phase was evaporated in vacuo anddichloromethane (400 ml) was added to the residue. The mixture wasstirred for 18 hours, dried (MgSO4), filtered and evaporated in vacuo.The residue was suspended in acetone (20 ml) and stirred for 18 hours.The solid was filtered off, washed with acetone and dried. This afforded0.31 g (38%) of the title compound as a solid.

M.p. 221°-223° C.

Calculated for C₂₃ H₂₆ N₂ O₃, HCl, 0.5H₂ O: C, 65.16%; H, 6.66%; N,6.61%; Found: C, 65.05%; H, 6.73%; N, 6.42%.

Example 8 (R)-1-(3-(5-Methyl-dibenzb,f!azepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride##STR10##

To a solution of 10-methoxy-5H-dibenz b,f!azepine (40.7 g, 0.182 mol,prepared as described in Swiss pat. 389,619) in dry tetrahydrofuran (400ml) kept under an atmosphere of nitrogen, n-butyl lithium (80 ml, 0.216mol, 2.7M in n-hexane) was added dropwise at -30° C. The reactionmixture was stirred 0.5 hour. Iodomethane (13.3 ml, 0.214 mol) dissolvedin dry tetrahydrofuran (50 ml) was added dropwise at -20° C. Thereaction mixture was allowed to reach 0° C. quenched with water (300 ml)and extracted with diethyl ether (2×250 ml). The combined organicextracts were washed with water (500 ml), saturated brine (100 ml) anddried (MgSO₄), filtered and the solvent evaporated in vacuo. Yield 43.5g (100%) of 5-methyl-10-methoxy-dibenz b,f!azepine.

5-Methyl-10-methoxydibenz b,f!azepine (43 g, 0.181 mol) was dissolved in2N hydrochloric acid (800 ml) and heated at reflux temperature for 1.5hour. The cooled reaction mixture was extracted with diethyl ether(2×400 ml). The combined organic extracts were washed with water (500ml), saturated brine (100 ml) and dried (MgSO₄), filtered and thesolvent was evaporated in vacuo. The crude product (39.5 g) was purifiedby column chromatography on silica gel (2×900 ml) using a mixture ofethyl acetate and heptane (10:1) as eluent. This afforded 21.5 g (53 %)of 10,11-dihydro-5-methyl-dibenz b,f!azepin-10-one.

M.p. 92°-93° C.

To an ethylmagnesium bromide solution (prepared from magnesium (2.3 g,0.094 mol) and ethylbromide (8.1 ml, 0.103 mol) and dry tetrahydrofuran(50 ml)) cooled on an icebath, a solution of 3-chloro-1-propanol (7.9ml, 0.094 mol) in dry tetrahydrofuran (50 ml) was added dropwise withstirring. After the addition was complete, the mixture was stirred for0.5 hour. Magnesium (2.3 g, 0.094 mol) and an iodine crystal were added.Stirring was continued at reflux temperature for 1.5 hour. To thismixture a solution of 10,11-dihydro-5-methyl-dibenz b,f!azepin-10-one(7.0 g, 0.031 mol) in dry tetrahydrofuran (75 ml) was added dropwise andthe reaction mixture was stirred at reflux temperature for 2 hours. Thecooled reaction mixture was quenched with saturated ammonium chloride(50 ml), water (50 ml) and extracted with ethyl acetate (2×100 ml). Thecombined organic extracts were washed with water (2×100 ml), saturatedbrine (100 ml) and dried (MgSO₄), filtered and the solvent wasevaporated in vacuo. The crude product (7 g) was purified by columnchromatography on silica gel (700 ml) using a mixture of ethyl acetateand heptane (1:2) as eluent. Yield 0.9 g (11%) of 3-(5-methyl-dibenzb,f!azepin-10-yl)-1-propanol.

¹ H NMR (200 MHz, CDCl₃) δ_(H) 1.90 (bs, 1H), 2.09 (dp, 2H), 3.32 (s,3H), 3.88 (t, 2H), 4.16 (t, 2H), 6.04 (s, 1H), 6.91-7.34 (m, 7H), 7.45(dd, 1H).

To a solution of 3-(5-methyl-dibenz b,f!azepin-10-yl)-1-propanol (0.8 g,3.01 mmol) and triethylamine (0.8 ml) in dichloromethane (25 ml),methanesulfonyl chloride (0.5 g, 4.52 mmol) dissolved in dichloromethane(5 ml) was added dropwise at 15° C. The reaction mixture was stirred atroom temperature for 2 hours and quenched with water (25 ml). Theorganic phase was separated and dried (MgSO4), filtered and evaporatedin vacuo. This afforded 1.0 g (97%) of methanesulfonic acid3-(5-methyl-dibenz b,f!azepin-10-yl)-1-propyl ester as an oil.

TLC: R^(f) =0.49 (SiO₂ : heptane/ethyl acetate=1:1).

A mixture of the above methanesulfonate (1.0 g, 2.91 mmol),(R)-3-piperidinecarboxylic acid ethyl ester tartrate (1.8 g, 5.82 mmol),dry potassium carbonate (2.4 g, 17.5 mmol), and methyl ethyl ketone (50ml) was heated at reflux temperature for 18 hours under an atmosphere ofnitrogen. Potassium iodide (0.2 g, 1.205 mmol) was added and the mixturewas heated at reflux for an additional 18 hours. The cooled reactionmixture was quenched with water (50 ml) and extracted with ethyl acetate(50 ml). The organic phase was washed with water (2×80 ml), saturatedbrine (80 ml), dried (MgSO₄), filtered and the solvent evaporated invacuo. The crude product (1.3 g) was purified by column chromatographyon silica gel (500 ml) using a mixture of ethyl acetate and heptane(2:1) and later on a mixture of ethyl acetate and triethylamine (96:4)as eluents. This afforded 0.87 g (74%) of (R)-1-(3-(5-methyl-dibenzb,f!azepin-10-yl)-1-propyl)-3-piperidine-carboxylic acid ethyl ester asan oil.

TLC: R_(f) =0.25 (SiO₂ : ethyl acetate/heptane=2:1).

The above ester (0.7 g, 1.73 mmol) was dissolved in a mixture of ethanol(25 ml) and water (15 ml), sodium hydroxide (83 mg, 2.08 mmol) was addedand the mixture was stirred at room temperature for 60 hours. Thesolvent was evaporated in vacuo and the residue dissolved in water (50ml) and washed with diethyl ether (50 ml). The aqueous phase wasacidified with concentrated hydrochloric acid until pH=1 and extractedwith dichloromethane (3×100 ml). The combined dichloromethane phaseswere dried (MgSO₄) and the solvent evaporated in vacuo. The residue wassuspended in a mixture of diethyl ether (10 ml) and acetone (10 ml) andstirred at room temperature for 18 hours. The solid was filtered off andwashed with diethyl ether and dried. This afforded 0.15 g (20%) of thetitle compound as a solid.

M.p. 222°-224° C.

Calculated for C₂₄ H₂₈ N₂ O₂, HCl, 1.25 H₂ O: C, 66.19%; H, 7.29%; N,6.43%; Found: C, 66.01%; H, 7.00%; N, 6.15%.

Example 9 (R)-1-(3-(6,7-Dihydro-5H-dibenz b,g!1,5!oxazocin-6-yl)-1-propyl)-3-piperidine-carboxylic aciddihydrochloride ##STR11##

3-(6,7-Dihydro-5H-dibenz b,g! 1,5!oxazocin-6-yl)-1-propanol (0.60 g, 2.2mmol, the compound is described in German Patent, DE 2044508 710519 andprepared in a similar way as described in J. Med. Chem., 11, 1968, 97for an analogous azocine) was suspended in dry toluene (20 ml). On anice bath and under a nitrogen atmosphere, triethylamine (0.9 ml) wasadded, followed by methansulfonyl chloride (0.3 ml) which was addeddropwise. The resulting mixture was stirred at room temperature for 2hours. Water (25 ml) was added followed by toluene (50 ml) anddichloromethane (50 ml). The phases were separated. The aqueous phasewas extracted with ethyl acetate (50 ml). The combined organic phaseswere evaporated in vacuo. Methyl ethyl ketone (75 ml) was added to theresidue, followed by (R)-3-piperidinecarboxylic acid ethyl estertartrate (1.00 g, 3.3 mmol), potassium iodide (0.36 g, 2.2 mmol), andpotassium carbonate (0.76 g, 5.5 mmol). The mixture was heated at refluxtemperature for 216 hours. After filtration on filter aid (hyflo), thesolvent was removed by evaporation in vacuo. The residue was purified bycolumn chromatography on silica gel (150 ml) using ethyl acetate aseluent. This afforded 0.33 g (37%) of (R)-1-(3-(6,7-dihydro-5H-dibenzb,g! 1,5!oxazocin-6-yl)-1-propyl)-3-piperidinecarboxylic acid ethylester as an oil.

TLC: R_(f) =0.10 (SiO₂ : ethyl acetate).

The above ester (0.19 g, 0.46 mmol) was dissolved in 96% ethanol (20 ml)and a solution of sodium hydroxide (0.57 g) in water (3 ml) was added.The mixture was stirred at room temperature for 2 hours and concentratedhydrochloric acid (0.4 ml) was added. Dichloromethane (100 ml) wasadded, followed by water (50 ml) and the phases were separated. Theaqueous phase was washed with dichloromethane (2×75 ml) and evaporatedin vacuo. Isopropanol was added to the residue and the mixture wasfiltered. The filtrate was evaporated in vacuo. The resulting solid wasredissolved in isopropanol and isopropyl acetate was added. Theprecipitate was filtered off. This afforded after drying, 0.16 g (78%)of the title compound as an amorphous solid. The product was furtherpurified for analysis by washing with first dichloromethane and thenacetone.

M.p. amorph

Calculated for C₂₂ H₂₈ N₂ O₃, 2 HCl, 1.1 H₂ : C, 58.31%; H, 6.80%; N,5.91%; Found: C, 58.78%; H, 7.26%; N, 5.53%.

Example 10 (R)-1-(3-(11,12-Dihydro-dibenz a,e!cycloocten-5-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride ##STR12##

To a solution of sodium hydride (2.7 g, 0.066 tool, 60% dispersion inoil) in ethanol (200 ml) was added triethyl phosphonoacetate (14.9 g,0.066 mol) and the reaction mixture was stirred at room temperature for0.5 hour. To the reaction mixture was added 5,6,11,12-tetrahydro-dibenza,e!cycloocten-5-one (12.3 g, 0.055 mol, prepared as described in J. Am.Chem. Soc., 77, 1955, 5078) and the reaction mixture was heated atreflux temperature for 18 hours. The solvent was evaporated in vacuo andthe residue was suspended in water (200 ml) and extracted with diethylether (2×200 ml). The combined organic extracts were washed with water(2×80 ml), saturated ammonium chloride (80 ml), dried (MgSO₄), filteredand the solvent was evaporated in vacuo. The crude product (15.7 g) waspurified by column chromatography on silica gel (800 ml) using a mixtureof ethyl acetate and heptane (1:10) as eluent. This afforded 7.7 g (48%)of 11,12-dihydro-dibenz a,e!cycloocten-5-acetic acid ethyl ester as anoil.

TLC: R_(f) =0.21 (SiO₂ : ethyl acetate/heptane=1:10).

To a solution of lithiumaluminum hydride (1.9 g, 0.050 mol) in drydiethyl ether a solution of the above ester (7.3 g, 0.025 mol) in drydiethyl ether (50 ml) was added. The reaction mixture was stirred atreflux temperature for 1.5 hour. The reaction mixture was cooled on aice bath and quenched by addition of water (2 ml), 20% sodium hydroxide(2 ml), and MgSO₄ successively. The resulting mixture was filtered andthe filtercake was washed with diethyl ether (2×100 ml). The phases wereseparated and the organic phase was evaporated in vacuo affording 6.3 g(100%) of 2-(11,12-dihydro-dibenz a,e!cycloocten-5-yl)-ethanol.

TLC: R_(f) =0.16 (SiO2: ethyl acetate/heptane=1:4). To a mixture of theabove alcohol (6.0 g, 0.024 mol) and triethylamine (6 ml) indichloromethane (100 ml), methanesulfonyl chloride (4.1 g, 0.036 mol)dissolved in dichloromethane (25 ml) was added dropwise at 15° C. Thereaction mixture was stirred at room temperature for 2 hours andquenched with water (50 ml). The organic phase was separated, dried(MgSO₄) filtered and evaporated in vacuo. This afforded 7.7 g (98%) ofmethanesulfonic acid 2-(11,12-dihydro-dibenza,e!cycloocten-5-yl)-1-ethyl ester as an oil.

A mixture of the above methanesulfonate (7.7 g), potassium cyanide (2.0g, 0.031 mol), and dry dimethylsulfoxide (100 ml) was heated at 60° C.for.1.5 hour under an atmosphere of nitrogen. The cooled reactionmixture was quenched with water (100 ml) and extracted with diethylether (2×100 ml). The organic extract was washed with water (2×80 ml),brine (80 ml), dried (MgSO₄), filtered and the solvent was evaporated invacuo affording 4.7 g (76%) of 3-(11,12-dihydro-dibenzoa,e!cycloocten-5-yl)-propionitrile as an oil.

TLC: R_(f) =0.72 (SiO₂ : ethyl acetate/heptane=1:2).

A mixture of the above propionitrile (3.6 g, 0.014 mol) and 50%potassium hydroxide was heated at reflux temperature for 42 hours. Tothe cooled reaction mixture water (300 ml) was added and the mixture waswashed with diethyl ether (100 ml). The aqueous phase was acidified topH=1 with concentrated hydrochloric acid and extracted with diethylether (2×200 ml). The combined organic extracts were washed with water(100 ml), brine (80 ml), dried (MgSO₄), filtered and the solvent wasevaporated in vacuo affording 2.9 g (75%) of 3-(11,12-dihydro-dibenzoa,e!cycloocten-5-yl)-1-propionic acid as an oil.

To a solution of lithiumaluminum hydride (0.7 g, 18 mmol) in drytetrahydrofuran (30 ml) the above propionic acid (2.6 g, 9.3 mmol) indry diethyl ether (30 ml) was added. The reaction mixture was stirred atreflux temperature for 1.5 hour. The reaction was cooled on a ice bathand quenched by addition of water (0.7 ml), and 20% sodium hydroxide(0.7 ml), successively. The resulting mixture was filtered and thefiltercake was washed with diethyl ether (2×100 ml). The phases wereseparated and the organic phase was evaporated in vacuo affording 2.6 g(100%) of 3-(11,12-dihydro-dibenz a,e!cycloocten-5-yl)-1-propanol as anoil.

TLC: R_(f) =0.34 (SiO₂ : ethyl acetate/heptane=1:2).

To a mixture of the above alcohol (2.0 g, 7.56 mmol) and triethylamine(2 ml) in dichloromethane (50 ml), methanesulfonyl chloride (1.3 g, 11.4mmol) dissolved in dichloromethane (10 ml) was added dropwise at 10° C.The reaction mixture was stirred at room temperature for 2 hours andquenched with water (50 ml). The organic phase was separated, dried (Na₂SO₄), filtered and evaporated in vacuo. This afforded 2.5 g ofmethanesulfonic acid 3-(11,12-dihydro-dibenz-a,e!cycloocten-5-yl)-1-propyl ester as an oil.

A mixture of the above methanesulfonate (2.5 g),(R)-3-piperidinecarboxylic acid ethyl ester tartrate (4.6 g, 15.1 mmol),dry potassium carbonate (6,3 g, 45.4 mmol), and methyl ethyl ketone (100ml) was heated at reflux temperature for 48 hours under an atmosphere ofnitrogen. The cooled reaction mixture was quenched with water (100 ml)and extracted with diethyl ether (100 ml). The organic extract waswashed with saturated brine (80 ml), dried (Na₂ SO₄), filtered and thesolvent evaporated in vacuo. The crude product (3.1 g) was purified bycolumn chromatography on silica gel (600 ml) using a mixture of ethylacetate/heptane (1:2) as eluent. This afforded 1.9 g of crude(R)-1-(3-(11,12-dihydro-dibenz a,e!cycloocten-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester. The ethyl ester wassuspended in water (150 ml) and concentrated hydrochloric acid was addedto pH=1. The aqueous phase was washed with diethyl ether (100 ml)basified to pH=8 with 20% sodium hydroxide and extracted with diethylether (2×100 ml). The combined organic extracts were washed with brine(80 ml), dried (MgSO₄), filtered and the solvent was evaporated in vacuoaffording 1.1 g (36%) of (R)-1-(3-(11,12-dihydro-dibenza,e!cycloocten-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl esteras an oil.

TLC: R_(f) =0.42 (SiO₂ : ethyl acetate/heptane=1:1).

A solution of sodium hydroxide (120 mg, 3.0 mmol) in water (10 ml) wasadded to the above ester (1.0 g, 2.5 mmol) dissolved in ethanol (25 ml),and the mixture was stirred at room temperature for 60 hours. Thesolvent was evaporated in vacuo and to the residue water (100 ml) wasadded. The aqueous mixture was washed with diethyl ether (2×50 ml)acidified to pH=1 with concentrated hydrochloric acid and extracted withdichloromethane (3×75 ml). The combined organic extracts were dried(MgSO₄), filtered and evaporated in vacuo. This afforded 0.67 g (66%) ofthe title compound as a solid.

Calculated for C₂₅ H₂₉ NO₂, HCl, 0.25 H₂₀ : C, 72.10%; H, 7.38%; N,3.36%; Found: C, 71.88%; H, 7.67%; N, 3.09%.

We claim:
 1. A compound of formula I ##STR13## wherein R¹ and R²independently are hydrogen, halogen, trifluoromethyl, hydroxy, C₁₋₆-alkyl or C₁₋₆ -alkoxy;Y is --CH₂ --N--CH₂ --, --CH₂ N--CH₂ --,--(C═O)--N--CH₂ --, or --CH₂ --N--(C═O)--, wherein only the underscoredatoms participate in the ring system; X is --C(R⁶ R⁷)--, --(C═O)--, or--N(R⁹)-- wherein R⁶, R⁷, and R⁹ independently are hydrogen or C₁₋₆-alkyl; p is 0; q is 0; r is 1, 2 or 3; m is 1 or 2; n is 1 when m is 1and n is 0 when m is 2; R³ and R⁴ each represents hydrogen or, when m is2, together may represent a bond; and R⁵ is --OH or C₁₋₆ -alkoxy; orapharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein R¹ and R² independently represent hydrogen, halogen orC₁₋₆ -alkoxy.
 3. A compound according to claim 2 wherein R¹ and R² arehydrogen.
 4. A compound according to claim 1 wherein r is
 2. 5. Acompound according to claim 1 wherein m is
 2. 6. A compound according toclaim 1 wherein R⁵ is --OH.
 7. A compound according to claim 1 whichis:(R)-1-(3-(11-Oxo-10,11-dihydro-5H-dibenzo b,e!1,4!diazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid; or apharmaceutically acceptable salt thereof.
 8. A compound according toclaim 1 which is:(R)-1-(3-(6,11-Dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid; or apharmaceutically acceptable salt thereof.
 9. A compound according toclaim 1 which is:(R)-1-(3-(6,11-Dioxo-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid; or apharmaceutically acceptable salt thereof.
 10. A compound according toclaim 1 which is:(R)-1-(3-(11-Oxo-6,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid; or apharmaceutically acceptable salt thereof.
 11. A compound according toclaim 1 which is:(R)-1(3-(5,11-Dihydro-10H-dibenzo b,e!1,4!diazepin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;1-(3-(6-Oxo-5,11-dihydro-5H-dibenzb,e!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid; orapharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising as active component a compound according to claim1 together with a pharmaceutically carrier or diluent.
 13. Thepharmaceutical composition according to claim 12 wherein the compound ispresent in an amount between 0.5 mg and 1000 mg per unit dose.
 14. Amethod of treating diabetic neuropathy, migraine, neurogenicinflammation, or rheumatoid arthritis in a subject in need of suchtreatment comprising administering to the subject an effective amount ofa compound according to claim
 1. 15. A method of treating insulinresistance in a subject in need of such treatment comprisingadministering to the subject an effective amount of a compound accordingto claim
 1. 16. A method of treating diabetic neuropathy, migraine,neurogenic inflammation, or rheumatoid arthritis in a subject in need ofsuch treatment comprising administering to the subject a pharmaceuticalcomposition according to claim
 12. 17. A method of treating insulinresistance in a subject in need of such treatment comprisingadministering to the subject a pharmaceutical composition according toclaim
 12. 18. A compound of formula I ##STR14## where R¹ and R²independently are hydrogen, halogen, trifluoromethyl, hydroxy, C₁₋₆-alkyl or C₁₋₆ -alkoxy;Y is --CH═C--CH₂ --, --CH₂ --C═CH--, --CH₂--CH--CH₂ --, --CH₂ --CH--CH₂ --, --CH₂ --C═CH--, or --CH ═C--CH₂ --,wherein only the underscored atoms participate in the ring system; X is--N(R⁹)-- where R⁹ is hydrogen or C₁₋₆ -alkyl; p is 0; q is 0; r is 1,2or 3; m is 1 or 2; n is 1 when m is 1 and n is 0 when m is 2; R³ and R⁴each represents hydrogen or, when m is 2, together may represent a bond;and R⁵ is --OH or C₁₋₆ -alkoxy; ora pharmaceutically acceptable saltthereof.
 19. A compound according to claim 18 wherein R¹ and R²independently represent hydrogen, halogen or C₁₋₆ -alkoxy.
 20. Acompound according to claim 19 wherein R¹ and R² are hydrogen.
 21. Acompound according to claim 18 wherein r is
 2. 22. A compound accordingto claim 18 wherein m is
 2. 23. A compound according to claim 18 whereinR⁵ is --OH.
 24. A compound according to claim 18 whichis:(R)-1-(3-(5-Methyl-dibenzb,f!azepin-10-yl)1-propyl)-3-piperidinecarboxylic acid; orapharmaceutically acceptable salt thereof.
 25. A compound according toclaim 18 which is:1-(3-(5-Methyl-5,11-dihydro-dibenzb,f!azepin-10-ylidene)-1-propyl)-3-piperidinecarboxylic acid; orapharmaceutically acceptable salt thereof.
 26. A pharmaceuticalcomposition comprising as active component a compound according to claim18 together with a pharmaceutically carrier or diluent.
 27. Thepharmaceutical composition according to claim 26 wherein the compound ispresent in an amount between 0.5 mg and 1000 mg per unit dose.
 28. Amethod of treating diabetic neuropathy, migraine, neurogenicinflammation, or rheumatoid arthritis in a subject in need of suchtreatment comprising administering to the subject an effective amount ofa compound according to claim
 18. 29. A method of treating insulinresistance in a subject in need of such treatment comprisingadministering to the subject an effective amount of a compound accordingto claim
 18. 30. A method of treating diabetic neuropathy, migraine,neurogenic inflammation, or rheumatoid arthritis in a subject in need ofsuch treatment comprising administering to the subject a pharmaceuticalcomposition according to claim
 26. 31. A method of treating insulinresistance in a subject in need of such treatment comprisingadministering to the subject a pharmaceutical composition according toclaim 26.